Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-08, Vol.106 (32), p.13481-13486
• Main Authors: Kawajiri, Kaname, Kobayashi, Yasuhito, Ohtake, Fumiaki, Ikuta, Togo, Matsushima, Yoshibumi, Mimura, Junsei, Pettersson, Sven, Pollenz, Richard S, Sakaki, Toshiyuki, Hirokawa, Takatsugu, Akiyama, Tetsu, Kurosumi, Masafumi, Poellinger, Lorenz, Kato, Shigeaki, Fujii-Kuriyama, Yoshiaki
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - metabolism; Animals; beta Catenin - metabolism; Biological Sciences; Cecal Neoplasms - metabolism; Cecal Neoplasms - pathology; Intestines - metabolism; Intestines - pathology; Ligands; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Proteasome Endopeptidase Complex - metabolism; Protein Processing, Post-Translational; Receptors, Aryl Hydrocarbon - deficiency; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction; Ubiquitination
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0902132106

Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of β-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent β-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Apc Min /+ mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.